Depressive Disorders

David A. Brent

V. Robin Weersing

In this chapter, we describe the nosology and epidemiology of unipolar depressive disorders in youth, risk factors for depression onset and recurrence, and the evidence base for psychosocial and pharmacological treatments. We conclude with suggested areas for future inquiry.

Clinical Picture

Depressive disorders in childhood and adolescence are characterized by core persistent and pervasive sadness, anhedonia, boredom or irritability that is functionally impairing, and relatively unresponsive to usual experiences that might usually bring relief, such as pleasurable activities and interactions and attention from other people. The single most important distinction between depression as an illness and the “normal ups and downs” of childhood and adolescence is that depression is associated with functional impairment, mediated through the intensity, duration, and lack of responsiveness of depressed mood and associated symptoms.

Depressive disorders exist on a continuum, and are classified on the basis of severity, pervasiveness, and presence or absence of mania (1). At the mildest end of the spectrum are adjustment disorders with depressed mood, which are mild, self-limited, and occur in response to a clear stressor. Depression not otherwise specified (NOS), also referred to as “minor” or subsyndromal depression, is diagnosed in the presence of depressed mood, anhedonia, or irritability, and up to three symptoms of major depression (2). Dysthymic disorder is a chronic condition with fewer symptoms than major depression, but lasts a minimum of one year. Major depression is the most severe condition, with either sad or irritable mood, or anhedonia, along with at least five other symptoms, such as social withdrawal, worthlessness, guilt, suicidal thoughts or behavior, sleep increase or decrease, decreased motivation and/or concentration, and increased or decreased appetite. Minor depression and dysthymic disorder are functionally impairing and are often precursors to major depression (2,3). Furthermore, dysthymia and major depression can coexist in a state referred to as “double depression,” which is associated with a particularly chronic course (3). Rarely, young patients with major depression also have psychotic symptoms such as auditory hallucinations or delusions, usually with self-derogatory, paranoid, or depressive content.

Comorbidity is the rule rather than the exception in depressed children and adolescents, especially in clinical samples (4). Anxiety is frequently a precursor of mood disorder and may also occur simultaneously with depression. ADHD and depression are also often comorbid and the two disorders may be cotransmitted in families (5). Alcohol, drug, and tobacco abuse are associated with depression, and longitudinal studies suggest a bidirectional causality, with substance abuse both leading to, and occurring as a consequence of, depression (6,7,8). Conduct disorder is frequently comorbid with depression, particularly in prepubertal samples (9). Comorbidity with depression may arise because sharing of risk factors that are common to both conditions. For example, the comorbidity of mood disorders and behavioral disorders and substance abuse may be due to common factors, such as parental substance abuse and criminality, exposure to family violence, and family discord (10). Comorbidity may also arise because a condition is either a precursor or a consequence to depression, in the cases of anxiety and tobacco use, respectively.

Descriptive Epidemiology

Estimates of Population Prevalence

The point prevalence of depressive disorders is 1–2% of prepubertal children and 3–8% of adolescents, with a lifetime prevalence by the end of adolescence of around 20% (11,12,13).

Gender Distribution and the Onset of Puberty

The 3:1 female predominance in mood disorders first emerges in adolescence (13). The higher female than male rate of depression after the onset of puberty may be due to: 1) increases in estradiol and testosterone associated with the onset of puberty in females, 2) higher rates of anxiety disorder and a tendency to rumination in females, which in turn predispose to depressive disorders, and 3) adolescent increases in interpersonal conflict that seem to be driven by genetic self-selection into risky environments and maladaptive responses to stress (14,15,16).

Age and Developmental Factors

Most typically, prepubertal depression has a set of risk factors and course similar to conduct disorder, with comorbid behavioral problems; family adversity such as family discord, parental criminality and parental substance abuse; and increased risk of antisocial disorder, but not depression in adult life (17,18,19). Less commonly, prepubertal depression is highly familial, with multigenerational loading for depression, with high rates of anxiety and bipolar disorder, and recurrences of mood disorder in adolescence and adulthood (18,20). Adolescent-onset depression is more likely to result in recurrent episodes in adult life (18,21). Recent work with structured diagnostic assessments has demonstrated the existence of depression even in preschool children, with the most prominent symptoms being sad or irritable mood, anhedonia, low energy, and change in level of activity (22).

Early-onset of puberty increases the risk of depression in girls (23). Other developmental factors that may contribute to an increased risk of depression after puberty include experimentation with tobacco, drugs and alcohol, decreased adult supervision and contact, and a greater physiological need for sleep, along with a tendency to actually obtain less sleep (6,7,8,24,25).

Risk Factors For Depression Onset and Recurrence

Genetic

Twin studies demonstrate that depressive symptoms have a greater concordance among monozygotic than among dizygotic twins, and a heritability of around 40–65%, with higher estimates of heritability in adolescent vs. prepubertal children (26,27,28,29,30). Both “bottom-up” and “top-down” family studies have shown a 2–4-fold increased risk of depression in first-degree relatives (31,32). Twin studies suggest a greater genetic component in adolescent vs. pre-pubertal onset depression, supportive of the view that very early onset depression may often be a response to a chaotic environment (30).

There is evidence that liability to depression is cotransmitted along with anxiety symptoms, with a heritability of 61–65% (32,33,34. Genes that influence the risk of anxiety may in turn lead to a higher rate of postpubertal depression by increasing sensitivity to life events, and also by increasing the likelihood of exposure to depressogenic life events (35,36). This formulation is consistent with the results of longitudinal studies (37,38), as well as with evidence that stressful life events and genetic diatheses (e.g., shorter allelic form of the serotonin transporter) interact to result in early-onset depression (39).

Cognitive Factors

Depressed individuals have been shown to have a negative view of self, future, and the world. Nondepressed individuals with these biases are more likely than those without these biases to develop depressive symptomatology when confronted with stressful life events (40,41,42). Cognitive distortions are associated with depression in both prepubertal children and adolescents, but only in adolescents is there some evidence that the distortions persist after the episode resolves (43). Depressed youth also exhibit “performance-based” disruptions in cognitive processes, such as greater difficulty than controls in remembering fearful faces (44), difficulty in inhibiting negative affect in response to distressing stimuli (45), and more global and less specific recall in tests of categorical autobiographical memory (46).

Familial/Environmental Risk Factors

Twin studies show that the effect of shared environment is at least as potent as are heritable factors (30). Parental depression may exert its deleterious effect on child mood disorder not only through genetic mechanisms, but also via modeling of cognitive distortions, and through either passive and withdrawn or hostile interactions (47,48). Family environmental risk factors for child depression, such as parental criminality, parental substance abuse, lack of family cohesion, and parent-child discord, may be most relevant in the absence of a family history of depression (49). However, in some studies, family discord and expressed emotion interact with a depressive diathesis to predict onset and recurrence (48,50). Greater chronicity and severity of maternal depression has been related to greater liability for child cognitive distortions and parent–child conflict, both of which increase liability and persistence for child depressive symptoms (48,51,52,53). Longitudinal studies show reciprocal interrelationships between maternal and child interpersonal difficulties, child behavior symptoms, cognitive distortions, and depressive outcome (40,48,54).

Neglect and child maltreatment increases the risk not only for depression, but also for substance abuse, disruptive disorder, posttraumatic stress disorder, and suicide attempt (55,56,57,58) The deleterious effects are strongest for more severe and chronic abuse, such as sexual abuse resulting in intercourse (55,56). Abuse may be associated with an earlier age of onset of depression (59). The effects of abuse may be long lasting, resulting in a lower rate of response to treatment and a higher risk for recurrent depression (60). However, it is difficult to isolate the effects of abuse from the other interrelated adverse aspects of parental functioning and home environment such as parental mood disorder, substance abuse, and criminality; lower education and income; marital discord; and association with deviant peers (56). The relationship between depression and abuse is much stronger in the presence of other family-genetic risk factors such as a family history of depression or the short form of the serotonin transporter gene (39,61,62).

Bereavement due to the loss of a sibling, parent, or close friend is associated with an increased risk for depression, especially if there is a positive family history for mood disorder (63,64,65).

Connection to family and to school, parental behavioral and academic expectations, and nondeviant peer group are all protective against several key health risk behaviors, including depression and suicidality (66).

Neuroendocrine

Provocative challenges that are putative measures of noradrenergic and serotonergic neurotransmission find differences in depressed children, both during episode and recovery, and in nondepressed children at high risk for depressive disorder (67,68,69,70). This pattern of finding suggests that these changes may be trait markers for early-onset depression. However, similar neuroendocrine responses to provocative serotonergic challenge may be found in those with adverse or abusive home environments, and with high levels of aggression (61,71).

Sleep

Subjective sleep complaints are a very prominent component of early-onset depression, although subjective complaints and objective observations of sleep in a sleep laboratory are not closely correlated (72). Increased cortisol secretion at the time of sleep onset may be related to adolescent depression (73). Decreased REM latency and increased latency of sleep onset were found more often in adolescents compared to prepubertal depressed children, and may be associated with greater severity, onset, and recurrence, although these findings may emerge only after a strict sleep/wake schedule has been imposed (74,75,76,77,78,79). Decreased sleep efficiency and delayed sleep onset have been reported to be associated with depressive episode persistence and recurrence (78,79,80).

Neuroimaging Studies

Structural imaging studies of adult subjects with early-onset, familial depression as well as in adolescents with depression have found reduced volume of the left subgenual prefrontal cortex (81,82,83). Preliminary studies
of female adolescent depressed twins suggest that this structural difference is genetically transmitted and may partially mediate the heritability of depression (26). Steingard et al.(84) reported decreased prefrontal cortex and increased third and fourth ventricular volume in depressed adolescents, although these findings may be a marker for the effects of chronicity. MacMillan (85) reported an increased pituitary and amygdala: hippocampal ratio size in depressed subjects compared to nondepressed controls, with amygdala: hippocampal ratio size correlated with the severity of anxiety symptoms. In line with these findings, Thomas and colleagues found, in response to fearful faces, increased amygdala activation in anxious children, and decreased amygdala activation in depressed children (86).

Course and Outcome

Episode Length and Recovery

The duration for depressive episodes ranges between 3 and 6 months for community samples, and between 5 and 8 months for referred samples (3,87). Factors associated with a longer episode duration include comorbid dysthymic disorder, comorbidity with anxiety disorder or substance abuse, greater initial severity of the depressive condition, current or past suicidal ideation or behavior, chronicity and number of episodes of parental depression, and family discord (51,88,89,90). In both clinical and community samples, around 20% of adolescents have a persistent depression of 2 or more years’ duration (11,88).

Risk for Recurrence

In one meticulously conducted study of the course of depressive disorder in children age 8 to 13 years old, the risk of recurrence was 40% in 2 years, and 72% in 5 years (89,91). Other longitudinal studies have shown that the risk for recurrent depression in adolescent depression followed forward is extremely high, with the rate of relapse or recurrence ranging between 30–70% in 1–2 years of follow-up (3,11,88,92,93). Risk factors for recurrence include early onset of mood disorder in parent, lack of complete recovery, defined as either subsyndromal depression or return to a dysthymic baseline, preexisting social dysfunction, history of sexual abuse, and family discord (3,11,50,60,88,90,94).

Risk for Bipolar Disorder

The risk of bipolar disorder in early-onset depression is estimated to be around 10-20%, and is higher in patients who present with hypomania in response to antidepressant medication, psychotic features, hypersomnia (in some studies), and a family history of bipolar disorder (95,96). Children and younger adolescents exposed to antidepressants may be at particularly high risk for manic switch (97).

Other Sequelae

Depressed youth are at increased risk for conduct disorder, personality disorders, alcohol, tobacco, and drug abuse, and suicidal behavior, as well as obesity, social adaptation, such as interpersonal problems, unfulfilling social relationships, and educational and occupational underachievement (6,7,8,10,11,98,99). These “sequelae” may be attributable to common factors that also contribute to risk for depression, such as parental criminality, parental substance abuse, physical or sexual abuse, and family discord (10). Alternatively, these negative sequelae may be residua of incomplete depressive symptom resolution (100).

Clinical Management

There are currently three treatments for adolescent depression with varying levels of empirical support, namely, antidepressant treatment, cognitive behavior therapy (CBT), and interpersonal therapy (IPT) (101). There has been considerably less research on treatment of prepubertal children with depression, although there is some support for the efficacy of antidepressants. Each of these three approaches will be discussed, followed by a recommendation for current “best practice” treatment of youth depression (102,103).

Antidepressant Medication

Evidence of Efficacy

Both the single largest placebo-controlled comparison study of tricyclic antidepressants (TCAs) and placebo, and a subsequent metaanalysis showed no difference between drug and placebo (104,105), while several studies have demonstrated efficacy with selective serotonin reuptake inhibitors (SSRI) antidepressants, especially using fluoxetine (106). This may be reflective of an overall developmental difference insofar as adolescents and younger adults may respond better to serotonergic agents, whereas older adults respond equally as well to serotonergic and to noradrenergic agents (107).

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